Optimization of a Parham Cyclization Aided by In Situ FTIR for an Enabling Synthesis of Tricyclo[6.2.0.03,6]deca-1,3(6),7-trien-2-amine

Abstract

An enabling synthesis of tricyclo[6.2.0.0^3,6]deca-1,3(6),7-trien-2-amine was developed starting from p-phenylenediacetic acid. The readily available p-phenylenediacetic acid was first converted in four steps to 1,4-dibromo-2,5-bis(2-bromoethyl)benzene, which was then subjected to Parham cyclization conditions. The mechanistic analysis of the Parham cyclization revealed that controlling the temperature and solvent environment was crucial. Process analytical technology (PAT) was used in the optimization of this intramolecular cyclization to identify the optimal temperature range for the halogen–metal exchange and intramolecular cyclization steps by means of a single kinetic experiment with increasing temperatures. A set of these small-scale experiments were conducted to fine-tune the reaction parameters and ensure scalability. Additionally, THF/n-hexane mixtures were utilized to balance solvent effects and solubility of the reactants, thereby minimizing competitive E2 elimination and affording the desired product in >60% assay yields. To complete the synthesis of tricyclo[6.2.0.0^3,6]deca-1,3(6),7-trien-2-amine, tricyclo[6.2.0.0^3,6]deca-1,3(6),7-triene was iodinated using N-iodosuccinimide and subsequently subjected to direct C–N coupling conditions.